Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
Dis Model Mech. 2011 Jan;4(1):126-34. doi: 10.1242/dmm.005694. Epub 2010 Nov 2.
It is seldom the primary tumour that proves fatal in cancer, with metastasis the fundamental pathological process for disease progression. Upregulation of Mena, a member of the evolutionarily conserved Ena/VASP family of actin cytoskeletal regulators, promotes metastasis and invasive motility of breast cancer cells in vivo. To complement in vitro studies of Ena/VASP function in fibroblasts, we manipulated levels of Ena, the Drosophila homologue of Mena, in migrating embryonic macrophages (haemocytes). Consistent with data from fibroblasts in vitro, Ena localises to regions of actin dynamics within migrating haemocytes, stimulates lamellipodial dynamics and positively regulates the number and length of filopodia. However, whereas Ena overexpression in fibroblasts reduces migration speeds, overexpressing Ena in haemocytes leads to a dramatic increase in migration speeds, more closely resembling the increased motility of breast cancer cells that overexpress Mena. We provide evidence that this key difference is due to spatial constraints imposed on cells within the three-dimensional environment of the embryo; this might explain how Mena can be used to promote aggressive migratory behaviour during cancer progression.
在癌症中，很少是原发性肿瘤导致死亡，转移是疾病进展的基本病理过程。Mena 是进化上保守的 Ena/VASP 家族肌动蛋白细胞骨架调节剂的成员，其上调促进了乳腺癌细胞在体内的转移和侵袭运动。为了补充 Ena/VASP 在成纤维细胞中的功能的体外研究，我们在迁移的胚胎巨噬细胞（血细胞）中操纵了 Ena，即 Mena 的果蝇同源物的水平。与体外成纤维细胞的数据一致，Ena 定位于迁移血细胞中肌动蛋白动力学区域，刺激片状伪足动力学，并正向调节丝状伪足的数量和长度。然而，Ena 在成纤维细胞中的过表达会降低迁移速度，而在血细胞中过表达 Ena 则会导致迁移速度的急剧增加，更类似于过度表达 Mena 的乳腺癌细胞的增加的运动性。我们提供的证据表明，这种关键差异是由于胚胎三维环境对细胞施加的空间限制造成的；这可能解释了为什么 Mena 可以用于促进癌症进展过程中的侵袭性迁移行为。
